Mutations in the presenilin-1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). Despite their relative rarity, their known genetic etiology makes them ideal for modeling in transgenic animals and it is hoped that their study will provide clues to the molecular pathways that are disturbed in the more common sporadic disease as well. Besides senile plaques (SPs) and neurofibrillary tangles (NFTs), AD brain also exhibits a microvascular pathology. PS1 null mutant mice exhibit vascular defects in the CNS during development. Recently we found that vascular development in PS1-/- brain can be rescued by selective expression of PS1 in neural progenitor cells. This rescue was surprising given the mesodermal origins of the cerebral vasculature and argued that PS1 mediates neural derived signals that are required for vascular development. PS1 FAD mutant transgenic mice also exhibit an age-related vascular pathology including mice in which an FAD mutation is expressed under the control of a neuron specific promoter (NSE). The pathology in the NSE FAD mice is intriguing since the transgene is not expressed in blood vessels providing an interesting parallel to the embryonic rescue and suggesting that neuronal expression of PS1 influences vascular homeostasis in adult brain. Hypoxia is a major regulator of vascular development as well as vascular homeostasis in adult tissues. Recently we found that expression of the hypoxia inducible factor 1 alpha (Hif1a) is decreased in PS1-/- embryos and that PS1-/- neurons and fibroblasts fail to activate Hlf1a in vitro. Hlf1a levels are also decreased in NSE FAD mutant transgenic mice. These observations have lead us to postulate that PS1 is essential for Hif1a activation and that Hif1a activation may be impaired in neurons harboring PS1 FAD mutants. Here we will explore these hypotheses through three specific aims directed at defining the biochemical basis for why PS1 is essential for Hif1a activation during hypoxia, determining whether failed signaling through the Hif1a may be a proximal cause of the vascular failure in PS1-/- embryos and examining whether hypoxia-induced signaling through the Hif1a pathway is impaired by PS1 FAD mutants. The public health relevance of this research lies in its exploration of a novel hypothesis concerning neurovascular signaling and the information that it might contribute to how this signaling is disrupted in AD. [unreadable] [unreadable]